Neural Control of Swallow-Breathing Transitions Across Healthy and Diseased States

Abstract

Swallowing and breathing share the same anatomical space, requiring precise neural coordination to prevent aspiration by ensuring these behaviors do not occur simultaneously. During swallowing, airway protection is achieved through coordinated activation of upper airway muscles that elevate the hyoid and larynx, invert the epiglottis, and close the vocal folds. Many of these same muscles also contribute to breathing by maintaining airway patency and regulating airflow. Because swallowing takes precedence over breathing and other airway behaviors, it can abruptly terminate inspiration and ongoing cough. Consequently, the neural circuits controlling these behaviors must not only suppress breathing during swallowing but also rapidly and seamlessly switch between behavioral states, allowing respiratory rhythm to resume and maintain homeostasis. Disruptions in swallowing, breathing, and their coordination are common in neurological disorders, including Rett Syndrome. However, the circuit-level mechanisms governing these transitions and the re-establishment of respiratory rhythmicity following swallowing remain poorly understood, and the effects of MECP2 mutations on these processes are largely unknown. Using optogenetic, chemogenetic, and behavioral approaches, we investigated how swallowing exerts dominance over breathing. To determine whether alterations in respiratory patterning result from swallow production itself or direct activation of brainstem neurons, we targeted cell-type-specific populations within key medullary regions involved in breathing and swallowing. Our findings demonstrate that swallow production itself—not activation of ChAT+Vglut2+ postinspiratory complex neurons—drives inspiratory inhibition and reorganization of respiratory patterning, revealing a hierarchical neural organization in which swallow circuits temporarily suppress and reconfigure respiratory network activity, thereby exerting dominant control over transitions between breathing and swallowing. This framework provides a foundation for understanding circuit-level disruptions in Rett syndrome and other neurological disorders.